Alzheimer Disease (AD) is the most common form of dementia in the elderly and currently affects more than four million people In the United States. Identifying the risks associated with the amyloid precursor protein, presenilin 1, presenilin 2, and apolipoprotein E genes has opened new avenues of research but because AD is a complex genetic disorder our understanding of the genetic basis of AD is far from complete. Nearly half of the genetic effect has not been explained and these unidentified genes are keys to defining the cause of this devastating disorder. The present application is a comprehensive effort to integrate statistical (linkage and association studies) and molecular (gene expression studies) genomic approaches toward identifying the remaining AD genes. We recently completed the largest AD genomic screen (455 families, 726 sibpairs) and identified 14 potential regions (MLOD or MLS is greater than or equal too 1.00) as locations for novel AD genes. The most interesting novel region is on 9p22 (MLOD = 3.45; MLS 3.30 in the overall and MLOD = 3.97; MLS = 4.42 in the autopsy confirmed subset[CONF]). We also found evidence supporting the recently reported linkage to chromosome 10q22 (MLOD=2.65; MLS=2.12 in the overall and MLOD=2.94; MLS=1.96 in the CONF). Combined with our continued evidence for a locus on chromosome 12, these three regions represent the highest priority locations for additional AD genes. To perform gene discovery in AD we will: (1) Extend our Family Resources to increase power and develop an independent confirmnation dataset; (2) Identify Locational Candidate Genes by confirming and narrowing the linkage regions and using the human genome sequence to enumerate all the genes within each region; (3) Identify Functional Candidate Genes using microarray and SAGE expression analysis on hippocampal tissue; (4) Test Locational and Functional Candidate Genes using association analyses on a large set of discordant sib pairs. Candidate genes identified through both specific aims 2 (location) and 3 (function) will be given highest priority for detailed examiantion. This approach integrates our family resources and our statistical and molecular expertise to identify the remaining genes in AD.